Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts.
J Thorac Oncol. 2020 Jul;15(7):1190-1199. doi: 10.1016/j.jtho.2020.02.011. Epub 2020 Mar 3.
We evaluated pulmonary adverse events observed within 7 days after drug initiation in phase 1 to phase 3 studies of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib.
The phase 1/2 study enrolled patients with advanced malignancies (dosage range, 30 mg-300 mg once a day); the phase 2 ALK in Lung Cancer Trial of AP26113 study treated patients with advanced ALK+ NSCLC postcrizotinib at either 90 mg once a day or 90 mg once a day for 7 days followed by 180 mg once a day; and the phase 3 ALK in Lung Cancer Trial of Brigatinib in first Line study treated inhibitor-naive patients with ALK+ NSCLC with brigatinib (180 mg once a day [with 7-day lead-in at 90 mg once a day]) or crizotinib (250 mg twice a day). Early-onset pulmonary events (EOPEs) at least possibly associated with brigatinib were captured.
In the phase 1/2, ALK in Lung Cancer Trial of AP26113, and ALK in Lung Cancer Trial of Brigatinib in first Line studies, 8% (11/137), 6% (14/219), and 3% (4/136) of patients, respectively, had at least possible EOPEs on brigatinib, with frequency appearing to increase with the starting dosage. Across trials, at the 90-mg once-a-day starting dosage (alone or step-up dosing), 4.5% of patients (20/440) had at least possible events (median time to onset, 2 days). A total of 12 patients (3%) had grade 3 or higher events leading to brigatinib discontinuation. Seven patients (1.5%) had grade 1 to grade 2 events and successfully continued brigatinib with or without brigatinib interruption, steroids, or supplemental oxygen. In pooled analysis of these trials, occurrence of EOPEs was significantly associated with continuous 10-year increases in patient age in unadjusted logistic regression analysis, and with Eastern Cooperative Oncology Group performance status and number of previous regimens in multivariate regression.
Clinically apparent EOPEs can occur within days of commencing brigatinib in a subset of patients with NSCLC. Identifying clinical parameters associated with a higher risk of developing such events may help mitigate these events.
我们评估了在间变性淋巴瘤激酶（ALK）抑制剂布加替尼的 1 期至 3 期研究中，药物起始后 7 天内观察到的肺部不良事件。
1/2 期研究入组了患有晚期恶性肿瘤的患者（剂量范围为 30mg-300mg，每日一次）；ALK 在肺癌中的 AP26113 试验治疗了接受克唑替尼治疗后进展的晚期 ALK+非小细胞肺癌患者，每日 90mg 一次或每日 90mg 一次连用 7 天后改为 180mg 一次；3 期 ALK 在肺癌中的 Brigatinib 一线治疗研究入组了未经抑制剂治疗的 ALK+非小细胞肺癌患者，接受布加替尼（每日 180mg[先以 90mg 每日一次导入 7 天]）或克唑替尼（每日 250mg，每日两次）治疗。至少可能与布加替尼相关的早期发生的肺部事件（EOPE）被捕获。
在 1/2 期、ALK 在肺癌中的 AP26113 试验和 ALK 在肺癌中的 Brigatinib 一线治疗研究中，分别有 8%（11/137）、6%（14/219）和 3%（4/136）的患者至少可能发生与布加替尼相关的 EOPE，且随着起始剂量的增加，频率似乎有所增加。在各试验中，在 90mg 每日一次起始剂量（单独或逐步增加剂量）下，4.5%（20/440）的患者至少可能发生事件（中位发病时间为 2 天）。共有 12 名患者（3%）因发生 3 级或更高的事件而停止使用布加替尼。7 名患者（1.5%）发生 1 级至 2 级事件，并成功继续使用布加替尼，无论是否中断布加替尼、使用类固醇或补充氧气。在这些试验的汇总分析中，EOPE 的发生与未经调整的逻辑回归分析中患者年龄连续 10 年的增加显著相关，与东部肿瘤协作组表现状态和先前治疗方案的数量在多变量回归中也相关。
在接受布加替尼治疗的非小细胞肺癌患者亚组中，在开始治疗后的几天内可能会出现临床明显的 EOPE。确定与发生此类事件风险较高相关的临床参数可能有助于减轻这些事件。
